人冠状病毒OC43 3CL蛋白酶和ML188作为广谱先导化合物的潜力:同源性建模和分子动力学研究

IF 2.222 Q3 Biochemistry, Genetics and Molecular Biology
Michael Berry, Burtram Fielding, Junaid Gamieldien
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引用次数: 16

摘要

冠状病毒3型凝乳胰蛋白酶样蛋白酶(3CLpro)是设计潜在抗冠状病毒抑制剂的有效靶点。蛋白酶活性位点和底物保护的高度同源性支持了广谱先导化合物的鉴定。之前的一项研究发现,化合物ML188(也称为16R)是严重急性呼吸综合征冠状病毒(SARS-CoV) 3CLpro的抑制剂。本研究将详细介绍人类冠状病毒OC43的3CLpro同源模型的生成,并确定16R形成广谱先导化合物的潜力。利用modeler软件对OC43 3CLpro和Schr?dinger预测了3CLpro活性位点内16R的结合构象和自由能。分子动力学进一步证实了配体的稳定性和氢键网络。在活性构象中成功生成了高质量的OC43 3CLpro同源模型。进一步的研究在生成的模型的活性位点重现了16R的结合姿态,其中其结合的自由能被证明与SARS-CoV的3CLpro相等,这是一种被实验证明可以抑制的受体。配体的稳定性随后被分子动力学证实。先导化合物16R可能是OC43和其他冠状病毒3CLpro的广谱抑制剂。本研究提供了OC43的3CLpro的原子结构,并支持了16R抑制作用的进一步实验验证。这些发现进一步证实了冠状病毒的3CLpro可以被广谱铅化合物抑制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Human coronavirus OC43 3CL protease and the potential of ML188 as a broad-spectrum lead compound: Homology modelling and molecular dynamic studies

Human coronavirus OC43 3CL protease and the potential of ML188 as a broad-spectrum lead compound: Homology modelling and molecular dynamic studies

The coronavirus 3 chymotrypsin-like protease (3CLpro) is a validated target in the design of potential anticoronavirus inhibitors. The high degree of homology within the protease’s active site and substrate conservation supports the identification of broad spectrum lead compounds. A previous study identified the compound ML188, also termed 16R, as an inhibitor of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) 3CLpro. This study will detail the generation of a homology model of the 3CLpro of the human coronavirus OC43 and determine the potential of 16R to form a broad-spectrum lead compound. MODELLER was used to generate a suitable three-dimensional model of the OC43 3CLpro and the Prime module of Schr?dinger predicted the binding conformation and free energy of binding of 16R within the 3CLpro active site. Molecular dynamics further confirmed ligand stability and hydrogen bonding networks.

A high quality homology model of the OC43 3CLpro was successfully generated in an active conformation. Further studies reproduced the binding pose of 16R within the active site of the generated model, where its free energy of binding was shown to equal that of the 3CLpro of SARS-CoV, a receptor it is experimentally proven to inhibit. The stability of the ligand was subsequently confirmed by molecular dynamics.

The lead compound 16R may represent a broad-spectrum inhibitor of the 3CLpro of OC43 and potentially other coronaviruses. This study provides an atomistic structure of the 3CLpro of OC43 and supports further experimental validation of the inhibitory effects of 16R. These findings further confirm that the 3CLpro of coronaviruses can be inhibited by broad spectrum lead compounds.

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来源期刊
BMC Structural Biology
BMC Structural Biology 生物-生物物理
CiteScore
3.60
自引率
0.00%
发文量
0
期刊介绍: BMC Structural Biology is an open access, peer-reviewed journal that considers articles on investigations into the structure of biological macromolecules, including solving structures, structural and functional analyses, and computational modeling.
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